title: Acetyl analogs of combretastatin A-4: synthesis and biological studies.
abstract: The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC(50) values in the sub-μM range. Analog 6t has an IC(50) of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 μM). This compound initiates microtubule depolymerization with an EC(50) value of 1.8 μM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity.
authors.affiliation: Department of Chemistry and the Division of Natural and Applied Sciences, Hope College 49423, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Babu
authors.forename: Megan
authors.initials: M
authors.lastname: Lee
authors.forename: Lauren
authors.initials: L
authors.lastname: Lee
authors.forename: Raymond
authors.initials: R
authors.lastname: Strobel
authors.forename: Olivia
authors.initials: O
authors.lastname: Brockway
authors.forename: Alexis
authors.initials: A
authors.lastname: Nickols
authors.forename: Robert
authors.initials: R
authors.lastname: Sjoholm
authors.forename: Samuel
authors.initials: S
authors.lastname: Tzou
authors.forename: Sameer
authors.initials: S
authors.lastname: Chavda
authors.forename: Dereje
authors.initials: D
authors.lastname: Desta
authors.forename: Gregory
authors.initials: G
authors.lastname: Fraley
authors.forename: Adam
authors.initials: A
authors.lastname: Siegfried
authors.forename: William
authors.initials: W
authors.lastname: Pennington
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Hartley
authors.forename: Cara
authors.initials: C
authors.lastname: Westbrook
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D013267:Stilbenes; C058728:fosbretabulin